A subject of the invention is new biphenyl compounds, their preparation process and the intermediates of this process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the invention is the compounds of general formula (I): 
in which [X] represent the following aromatic carbocycles: 
in which R1 represents an alkyl radical containing from 1 to 4 carbon atoms or a hydrogen-atom, R2 represents an alkyl 35 radical containing from 1 to 4 carbon atoms or a hydrogen atom, R3 represents a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4 carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms, R4 in para or meta position represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl, alkenyl or alkynyl radical containing at most 4 carbon atoms, an alkoxy, alkylthio radical in which alkyl contains from 1 to 4 carbon atoms, an xe2x80x94NRARB group in which AA and RB identical or different represent a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms or form together with the nitrogen to which they are linked a saturated heterocycle with 5 or 6 members optionally containing a second heteroatom chosen from nitrogen, oxygen and sulphur, their xe2x80x94NRARB group being optionally in oxidized form, a group of general formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRARB in which n is an integer which varies from 2 to 7 and in which xe2x80x94NRARB is as defined previously, R5 represents a hydrogen atom or a halogen atom, R6 and R7 identical or different represent a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4 carbon atoms, or a phenyl radical optionally substituted in meta or para position by an R4 radical as defined previously as well as the addition salts with acids or bases, with the exception of the compounds of formula (I) in which [X] represents the group (A) in which R1, R2, R3 are hydrogen atoms and R4 represents a hydroxyl radical and those in which [X] represents the group (B) in which R5, R6 and R7 are hydrogen atoms or R5 and R6 are hydrogen atoms and R7 represents an alkyl radical containing from 1 to 4 carbon atoms.
When R1, R2, R3, R4, R6, R7, AA and RB represent an alkyl radical containing from 1 to 4 carbon atoms, it is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical. When R3, R4, R5, R6 and R7 are halogen atoms, it is fluorine, chlorine, bromine or iodine. Preferably, it is chlorine. When R4 is an alkenyl radical containing at most 4 carbon atoms, preferably it is a vinyl or propenyl radical. When R4 is an alkynyl radical containing at most 4 carbon atoms, preferably it is an ethynyl or propynyl radical. When R3 or R4 represent an alkyloxy radical containing from 1 to 4 carbon atoms, preferably it is a methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy radical. When R4 is an alkylthio radical containing from 1 to 4 carbon atoms, preferably it is a methylthio, ethylthio, propylthio, isopropylthio or butylthio radical. When R4 is an NRARB radical in which RA and RB identical or different represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, preferably it is an amino, methylamino, ethylamino, dimethylamino, diethylamino or methylethylamino radical. When R4 is an xe2x80x94NRARB group in which AA and RB form with the nitrogen a saturated heterocycle, preferably it is pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino groups, each of these amino groups being optionally in oxidized form.
Naturally the invention extends to the salts of the compounds de formula (I), in particular when the compounds of formula (I) contain an amino function. These are the salts formed for example with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonics such as methane- and ethanesulphonics, arenesulphonics, such as benzene and paratoluene sulphonics and arylcarboxylics.
These are also the salts formed under the action of a base or an alkali or alkaline-earth metal, in order to obtain for example derivatives such as sodium or potassium alcoholate or derivatives such as potassium or sodium phenolate.
A more particular subject of the invention is the compounds of general formula (I) as defined previously in which [X] is the aromatic carbocycle of general formula (A).
A more particular subject of the invention is the products of general formula (I) as defined previously in which [X] is the aromatic carbocycle of general formula (B).
A more particular subject of the invention is the products of general formula (I) as defined above, corresponding to general formula (Ixe2x80x2): 
in which Rxe2x80x21 Rxe2x80x22 and Rxe2x80x23 represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, Rxe2x80x24 in meta or para position represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical, an xe2x80x94NRARB group or an xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRARB group, n, AA and RB being as defined previously, as well as the addition salts with acids. When Rxe2x80x24 is an xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRARB group, it is preferably the xe2x80x94Oxe2x80x94(CH2)2-NMe2 group.
A more particular subject of the invention is the products of general formula (I) as defined previously corresponding to general formula (Ixe2x80x2) in which Rxe2x80x21, Rxe2x80x22 and Rxe2x80x23 are hydrogen atoms.
A quite particular subject of the invention is the compound of general formula (I) as defined previously in which R6 represents a halogen atom or an xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)2 group and R7 represents a hydrogen atom.
A quite particular subject of the invention is the compound of general formula (I) as defined above the names of which follow:
5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxyphenyl) 2-naphthalenol,
xe2x80x941,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol,
5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol.
A subject of the invention is also a preparation process for the products of formula (I) as defined above characterized in that a product of formula (II): 
in which [X] is as defined previously, Pxe2x80x2 represents a protective group, and G represents a halogen atom or an OSO2CF3 group is subjected to the action, in the presence of a catalyst, of a product of formula (III): 
in which Y represents a halogen atom, a B(OH)2 group or an Sn(R)3 group, in which R represents an alkyl group containing from 1 to 8 carbon atoms and P represents a protective group identical to or different from Pxe2x80x2, in order to obtain a product of formula (IV): 
in which P, Pxe2x80x2 and [X] have the same meaning as previously, which product of formula (IV) is subjected to one or more deprotection reactions in order to obtain the product of formula (I) as defined previously which, if appropriate is subjected to the action of an acid or base in order to obtain the corresponding salt.
The formation of the biphenyls of formula (IV) by coupling the aromatic compound of formula (II) with the aromatic compound of formula (III) is carried out in the presence of a catalyst chosen from the derivatives of palladium or in the presence of copper in the case where Y is an iodine atom and can therefore be carried out under the conditions described in the following articles:
A. Huth, I. Beetz and I. Schumann Tetrahedron (1989) 45 6679: Conditions: Na2CO3 2M/Pd(P"PHgr"3)4/Toluene/LiCl/EtOH/xcex94)
J. K. Stille Ang. Chem. Int. Ed. (1986) 25 508: Conditions: Pd(P"PHgr"3)4/LiCl/Dioxane/xcex94)
T. Oh-e, N. Migawa and A. Suzuki J. Org. Chem. (1993) 58 2201-2208: Conditions: K3Po4/KBr/Pd(Pxcex943)4/Dioxane/xcex94)
P. E. Fank Chem. Rev. (1964) 38 139: Conditions: Cu/DMF/120xc2x0 C. in the case where Y is an iodine atom.
E. Erdik Tetrahedron (1992) 48 9577: Conditions: nBuLi/THF/xe2x88x9278xc2x0 C.-2) ZnCl2-3) ArBr/Pd(P"PHgr"3)4/)xcex944)HCl/MeOH.
A subject of the invention is also a preparation process for products of formula (I) in which [X] is the aromatic carbocycle of formula (A) as defined above characterized in that a product de formula (V): 
in which R4 and P are as defined previously, is subjected to the action of the methylvinylketone of general formula (VI): 
in which R1, R2 and R3 are as defined previously, in order to obtain the product of formula (VII): 
in which R1, R2, R3, R4 and P are as defined previously, which is subjected to the action of a dehydration and aromatization reagent in order to obtain the product of formula (VIII): 
in which R1, R2, R3, R4 and P are as defined previously, which is subjected to the action of a deprotection reagent in order to obtain the products of formula (I) in which [X] is the aromatic carbocycle of formula (A) which, if desired, is subjected to the action of an acid in order to obtain a corresponding salt.
The protective groups P or Pxe2x80x2 are preferably chosen from an alkyl radical containing from 1 to 4 carbon atoms, a benzyl group and an RCRDRESi group, in which RC, RD and RE identical or different represent an alkyl radical containing from 1 to 4 carbon atoms or a phenyl group. It will be quite particularly methyl, phenyl, terbutyldimethylsilyl and terbutyldiphenylsilyl radicals.
The action of the methylvinylketone of general formula (III) on the product of formula (II) is preferably carried out in the presence of a base such as potash in a dioxane/water mixture.
The dehydration and aromatization reaction is carried out for example using a mineral acid such as phosphoric acid at a temperature of 150xc2x0 C. for 4 hours.
The deprotection reactions are the standard deprotection methods known to a person skilled in the art. A fairly complete list is found in the following work: Protective groups in organic synthesis T. W greene, John Wiley and sons (1981).
By way of example, when P or Pxe2x80x2 represent a methyl radical the deprotection reaction can be carried out by the action of tribromoborane in dichloromethane or hydrochloric acid in pyridine. When P or Pxe2x80x2 represents a benzyl group a catalytic hydrogenation or a hydrolysis can be carried out with trifluoroacetic acid. When P or Pxe2x80x2 represents a silyl group the deprotection can be carried out with tetra-butylammonium fluoride (TBAF) in tetrahydrofuran (THF).
Salification by an acid or a base is carried out under standard conditions. The operation is carried out for example with hydrochloric acid, in an ethereal solution.
The compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids or bases are particularly useful products from a pharmacological point of view.
They are the original ligands of the oestrogen receptor. As such, they can be used in the treatment of disorders linked to hypofolliculinia, for example, amenorrheas, dysmenorrheas, repeated abortions, premenstrual disorders, in the treatment of certain oestrogen-dependent pathologies such as prostatic adenomas or carcinomas, mammary carcinomas and their metastases or in the treatment of benign tumors of the breast, both as an antiuterotrophic as well as in replacement treatment of symptoms linked to the menopause and in particular osteoporosis.
Therefore, a subject of the invention is, as medicaments, the products of formula (I) as described previously as well as their addition salts with pharmaceutically acceptable acids or bases.
A more particular subject of the invention is, as medicaments, the compounds of formula (I) as described previously corresponding to general formula (Ixe2x80x2) as described previously as well as the addition salts with pharmaceutically acceptable acids or bases.
A quite particular subject of the invention is, as medicaments, the following products of formula (I):
5-[4-[2-(dimethylamino) ethoxy] phenyl] 6-(4-hydroxy-phenyl) 2-naphthalenol,
5-chloro-6-(4-hydroxyphenyl)2-naphthalenol, 1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol.
The invention extends to the pharmaceutical compositions containing at least one medicament as defined above as active ingredient.
The compositions of formula (I) are used by digestive, parenteral or local route, for example by percutaneous route. They can be prescribed in the form of plain or sugar-coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microspheres, implants, patches which are prepared according to the usual methods.
The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
The dose varies according to the illness treated and the administration route: it can be, for example, from 1 mg to 100 mg per day by oral route, for an adult.
The products of general formula (V) as defined above are obtained by the action of the product of general formula (IX): 
with a product of general formula (X): 
in the presence of a strong base such as LDA (lithium diisopropylamide).
This reaction is described in:
S. HUNIG et al. Chem. Ber. (1980) 113, 324-332
The products of formula (X) are obtained by the action of trimethyl silyl cyanide in the presence of a Lewis acid such as ZnI2, on the corresponding aldehyde of general formula (XI): 
This reaction is described in Synthesis (1980) p. 861-868. The protected products of formula (IX) are obtained from parahydroxy benzaldehyde by standard protection methods for alcohols described in the work by T. W. Greene mentioned above.
The products of formulae (II), (III), (IX), (X) and (XI) are commercial products or are easily accessible by standard functionalization methods for aromatic compounds known to a person skilled in the art.
The products of formula (VI) are also easily accessible to a person skilled in the art.
The products of formula (V) in which R4 is an alkyloxy containing from 1 to 4 carbon atoms in para position and P is an alkyl containing from 1 to 4 carbon atoms, are known and are described in the following references: Chemical Abstract: 65-10442b, 112-148858n, 59-9865f.
Finally, a subject of the invention is, as new industrial products and in particular as new intermediate products necessary for the implementation of the invention, the products of general formulae (IV), (V), (VII) and (VIII) as defined previously, with the exception of the products of formula (V) in which R4 is an alkyloxy containing from 1 to 4 carbon atoms or a halogen atom and P is an alkyl radical containing from 1 to 4 carbon atoms and with the exception of the products de formulae (VII) and (VIII) in which R4 is a methoxy radical, P is a methyl radical and R1, R2 and R3 are hydrogen atoms, and with the exception of the products of formula (IV) in which P and Pxe2x80x2 are methyl or acyl radicals, X represents the group B in which R5, R6 and R7 are hydrogen atoms.